Autoinflammatory diseases are a group of related conditions that include Muckle-Wells Syndrome (MWS), Familial Cold Autoinflamammatory Syndrome (FCAS) (also known as Familial Cold Urticaria or FCU), Familial Mediterranean Fever (FMF), Chronic Infantile Neurological Cutaneous and Articular Syndrome (CINCAS), a.k.a. Neonatal Onset Multisystem Inflammatory Disease (NOMID), TNFR1-Associated Periodic Syndrome (TRAPS), Hyper-IgD periodic fever Syndrome (HIDS), and Blau's syndrome (Gumucio et al., Clin. Exp. Rheumatol. 20: S-45-S-53, 2002).
These conditions have distinct genetic and phenotypic characteristics, but share certain features of their clinical presentation, including fever, urticaria, arthralgia, serositis, systemic amyloidosis as common complication, robust acute phase response and prominent neutrophilia in affected tissues.
These conditions are caused by mutations in the genes encoding various proteins involved in cellular signaling, notably those involved in regulation of activation of the interleukin-1β converting enzyme (ICE, a.k.a. caspase-1). ICE is a protease that converts the inactive precursor, pro-interleukin-1β (pro-IL-1β) to the active cytokine interleukin-1β (IL-1β), as well as pro-IL-18 to mature, active IL-1β. Among these modulatory genes & proteins, for example, is the gene CAIS1, which codes for the protein cryopyrin. Mutations of this gene and alteration of cryopyrin alters ICE activation, the consequent processing of pro-IL-1β to IL-1β and causes MWS and FCAS (Hoffman et al., Nat. Genet. 29: 301-305, 2001).
The critical role of IL-1β in the etiology of MWS (and by inference in FCAS, FMF, CINCAS, NOMID, TRAPS, HIDS and other autoinflammatory diseases and conditions) is illustrated by the demonstration that patients with MWS respond to treatment with recombinant human interleukin-1 receptor antagonist (rhuIL-1Ra, anakinra) with a dramatic, rapid and sustained reduction in clinical inflammatory symptoms, reduction of serum amyloid A (an acute phase inflammatory reactant) and urinary excretion of amyloid. This treatment, although effective, is limited in its use because it requires daily injection of the therapeutic agent.
Profound clinical improvement in response to anakinra may be an indicator that IL-1 is the key inflammatory cytokine underlying disease states, and indeed that such disease states are in fact autoinflammatory syndromes whose underlying genetic basis has yet to be determined. Examples include systemic-onset juvenile idiopathic arthritis (soJIA), also known as Still's disease, and the macrophage activation syndrome. The present invention also encompasses these indications.
The present invention describes the use of inhibitors of ICE/caspase-1, whether selective for ICE/caspase-1, or broadly active on a range of other caspases (2-14). This treatment, by inhibiting ICE and inhibiting IL-1β production will reduce the symptoms and other disease conditions of MWS, FCAS, FMF, CINCAS, NOMID, TRAPS, HIDS and other autoinflammatory diseases, conditions or syndromes.
Although anakinra has been shown to be effective in treating Muckle-Wells syndrome, Familial Cold Autoinflammatory Syndrome, Hyper-IgD syndrome and systemic onset Juvenile idiopathic Arthritis, anakinra is a protein and it therefore does not possess ideal pharmaceutical properties. Therefore, there is a need for small molecule, orally-active ICE inhibitors for treating certain diseases. Such compounds would be extremely useful in treating the aforementioned disease states where ICE plays a role.